Am J Ophthalmol. 2019 Feb 4. pii: S0002-9394(19)30048-0. doi: 10.1016/j.ajo.2019.01.027. [Epub ahead of print]
The location of exon 4 mutations in RP1 raises challenges for genetic counselling and gene therapy.
Mutations in the photoreceptor gene RP1 lead to recessive or dominantly inherited retinitis pigmentosa (RP). Since the dominantly inherited phenotype is generally milder than recessive cases, it raises the possibility that it could arise by haploinsufficiency, however most mutations are in the terminal exon 4, which would be predicted to generate truncated proteins. We therefore assessed a cohort of RP patients with confirmed mutations in RP1 in order to examine the genetic basis of the exon 4 mutations.
Observational case series METHODS: A retrospective review of 15 patients, aged between 36 and 84, with RP1 mutations in exon 4 confirmed by Sanger sequencing. All patients underwent full ophthalmic examination.
Two patients had homozygous mutations in RP1, p.(Glu1526*) and p.(Ser486fs) and presented with severe early onset retinal degeneration. Their first-degree relatives were unaffected. Thirteen patients had dominantly inherited retinitis pigmentosa presenting in adult life with a rod-cone dystrophy phenotype. Four novel mutations were identified. All mutations were predicted to produce truncated RP1 protein of variable lengths as follows: p.(Arg677*), p.(Gln679*), p.(Leu722*), p.(Ile725Argfs*6), p.(Ser734*)x2, p.(Leu762Tyrfs*17)x2, p.(Leu866Lysfs*7)x2, p.(Arg872Thrfs*2)x2 and p.(Gln917*).
The RP1 protein with a predicted length between 677 and 917 amino acids appears to have a dominant negative effect, whereas protein shorter than this (486 amino acids) or longer (1526 amino acids) leads to a more severe phenotype but only in homozygous individuals. Since mutations at various points along exon 4 have divergent consequences, genetic testing alone may be insufficient for counselling but recessive inheritance should be considered likely in severe early onset cases.
Copyright © 2019. Published by Elsevier Inc.